Hepatocellular Adenoma (Hepatic Adenoma)

Hepatocellular adenomas (HCAs) are also known as hepatic adenomas, telangiectatic focal nodular hyperplasia (FNH) or, less commonly, liver cell adenomas. They are rare, benign tumors of epithelial origin and occur in less than 0.007-0.012% of the population.[1] HCAs are most often found in women of childbearing age and are strongly associated with estrogen exposure, most commonly in the form of oral contraceptive pills (OCPs).[2] The use of OCPs in women reflects an up to 30-40-fold increase in incidence; the overall incidence in women taking OCPs has been estimated at 34 per million, whereas it is about 1-1.3 per million in women not taking OCPs.[3]  However, more recent epidemiologic studies are lacking.

The incidence of HCAs dramatically increased following the introduction of OCP medications in the 1960s. Prior to this, a study by Edmonson reported finding only two hepatic adenomas among 50,000 autopsy specimens at Los Angeles County Hospital between 1907 and 1958.[4] In 1973, Baum et al first suggested an association between hepatic adenomas and OCPs.[5] Klatskin[6] and Rooks et al[3] reported that the greatest risk occurred in women older than 30 years taking OCPs for longer than 5 years, but in 10% of patients, exposure may be as short as 6-12 months. Cherqui et al also reported that hepatic adenomas are occasionally diagnosed after discontinuation of OCPs,[7] although they generally tend to regress following discontinuation.[1]

In women using OCPs, adenomas were found to be more common in patients taking OCPs containing higher doses of estrogen and with prolonged use (73.4 mo) when compared with matched controls (36.2 mo) (P < 0.001).[8]  As reported by Edmonson et al, decreases in dosages and the types of hormones contained in OCPs since their introduction have led to a reduction in hepatic adenoma incidence[9] ; however, other factors are becoming more prominent in HCA formation.[10] Currently, benign liver tumors including HCAs may be detected more frequently, owing to the increased routine use of medical imaging.[10]

Other conditions associated with alterations in steroid exposure are implicated, including anabolic androgenic steroid use,[11] endogenous steroid exposure,[12]  polycystic ovarian syndrome (PCOS),[13] and Klinefelter syndrome.[14] HCAs are also associated with androgenic steroid use for medical conditions including paroxysmal nocturnal hemoglobinuria[15] and aplastic anemia.[16]  These adenomas are known to enlarge during pregnancy.[17] Rarer HCA associations have been noted in familial adenomatous polyposis,[18] mature onset diabetes of the young (MODY) 3,[19] and cases of iron overload such as beta-thalassemia[20] and primary hemochromatosis.[21]

Glycogen storage diseases (GSDs) are also a known risk factor for HCA development, most often occurring with multiple lesions and early onset (age < 20 years), and have a 2:1 male-to-female ratio.[22] Based on limited case series, the incidence ranges between 22% and 75% in type 1 GSD and 25% in type 3 GSD.[23, 24]

Obesity and features of metabolic syndrome (insulin resistance/diabetes, hypertension, and hyperlipidemia) are also increasingly recognized as HCA risk factors.[25] Obesity has been linked with the development of multiple and bilobar hepatic adenomas[25] and this association has been shown to be independent of OCP use, although obese patients using OCPs are at increased risk for these lesions as well.[25] Importantly, HCA progression to hepatocellular carcinoma (HCC) is of particular concern in men, in whom the risk of transformation is up to 10 times the rate seen in women, with the presence of metabolic syndrome being the primary factor.[26]

HCAs may be single or multiple, and they may occasionally reach a size larger than 20 cm.[27] Hepatic adenomatosis has been historically defined as at least 10 lesions, however, note that many patients with over three HCAs go on to develop more, and thus the definition can be applied to patients with four or more lesions.[28] Hepatic adenomatosis develops at equal frequency in either sex, has strong associations with GSD, anabolic steroids, and metabolic syndrome.[25, 29]

Major subtypes of hepatic adenomas have been defined to identify tumors at greatest risk of malignant transformation and hemorrhage.[30] This subclassification includes HCA inactivated for hepatocyte nuclear factor 1α (H-HCA), representing 30-40% of HCAs; inflammatory adenoma (I-HCA), representing 40-55% of HCAs; β-catenin activated HCA (β-HCA), representing 10-20% of HCAs; and unclassified HCA, representing 5-10% of HCAs.[20]

Among the subclassifications, β-catenin activation may promote tumor development, specifically HCC, especially when associated with coexisting I-HCA.[31, 32, 33, 34]  Evidence also exists to suggest obesity may cause an increase in the I-HCA and β-catenin activated-inflammatory HCA subgroups.[35]

Since Baum et al first suggested oral contraceptive pills (OCPs) to be a causal factor in hepatocellular adenoma (HCA) (hepatic adenoma) formation in 1973,[5] the role of both female and male sex hormones have been generally accepted as main factors in the the pathogenesis of these adenomas, although the exact mechanism is unclear. Nuclear estrogen receptors in HCAs have been identified in higher concentrations than in the surrounding hepatic tissue, suggesting increased responsiveness to estrogenic hormones.[36] However, this remains controversial, as adenomas can occur in males and children without predisposing risk factors, and other studies have not identified significant concentrations of receptors even with the use of monoclonal antibodies.[37] Rebouissou et al[38] and Bioulac-Sage et al[32, 39] postulated that hepatic adenomas are monoclonal tumors that develope from an interaction between gene defects and environmental changes such as OCPs and steatosis.

In addition to environmental factors, hepatic adenomas result from specific genetic mutations, with each subtype bearing significant clinical implications. There also remains an unclassified subtype of HCA, representing up to 5-10% of HCAs, without specific gene mutations or morphologic definitions.[20]

In HCA inactivated for hepatocyte nuclear factor 1α (HNF1A, also referred to as TCF1) (H-HCA), biallelic inactivation of HNF1A renders this tumor suppressor gene inactive, leading to predisposition for HCA formation in mature onset diabetes of the young (MODY) 3 and liver adenomatosis.[40] Typically, there is a female predominance.[41] Inactivation of HNF1A results in alterations in protein expression, with a characteristic loss of liver fatty acid binding protein (LFABP) in H-HCA compared to the surrounding hepatic tissue as a prime example, helping in the differentiation of micronodules from hepatic steatosis.[40]

I-HCAs are characterized by a variety of gene mutations, all of which result in activation of the JAK/STAT pathway.[31] They feature an inflammatory response with hepatocyte cystoplasm exhibiting C-reactive protein (CRP) and serum amyloid A (SAA), and they have associations with obesity and alcohol use.[2, 20] Genetic mutations activating the JAK/STAT pathway in I-HCA are generally mutually exclusive. The predominant form present in 65% of cases is a gain of function mutation of interleukin 6 signal transducer gene (IL6ST), which encodes glycoprotein (gp) 130, an IL-6 receptor component, which results in activation of STAT3 and subsequent inflammatory response.[20] I-HCA subtype was previously referred to as telangiectatic focal nodular hyperplasia (FNH), as it was thought to be a type of FNH; however, further investigation showed these lesions are more closely related to hepatic adenoma and thus they are now characterized as I-HCA.[42, 43]

In β-HCA, activating mutation of the β-catenin1 gene (CTNNB1) activates the Wnt/β-catenin pathway, which plays a significant role in liver development. Mutations of the Wnt/β-catenin pathway are also seen in hepatocellular carcinomas (HCCs), possibly explaining their stronger association with HCC development.[40] Both β-HCA and I-HCA with CTNNB1 mutation have an increased risk for malignant transformation. β-HCA subtype is seen more often in males, which may explain the increased incidence of malignant transformation in this population.[20]

In 2017, it was noted that an additional mutation in INBHE/GL1, resulting in sonic hedgehog activation in HCA (shHCA), is significantly associated with histologic hemorrhage and symptomatic bleeding, whereas a hepatic adenoma size of at least 5 cm, the current defining HCA risk factor for hemorrhage, was significantly associated with histologic hemorrhage alone. These findings show further delineation of subtypes may result in improving avoidance of such complications.[41] Up to eight subtypes have been identified following the most recent European Association for the Study of the Liver (EASL) guideline update, with two forms of mixed I-HCA/β-HCA and two forms of β-HCA.[41]

The increasing knowledge of genetic mutations in hepatic adenoma has shed light on possible mechanisms that could lead to HCA and malignant transformation in type 1 glycogen storage disease (GSD), which is most often of the I-HCA subtype.[20] GSD-related adenoma formation and progression have been reported to slow with dietary manipulation.[44] However, a study by Kishnani et al showed the most significant chromosomal aberration of simultaneous gain of 6p and loss of 6q could be high risk in the progression from HCA to HCC, regardless of metabolic control.[45]

Insulin and glucagon appear to play a role in HCA formation. Reznik et al described a germline mutation of HNFα in two families that had both diabetes mellitus and liver adenomatosis.[19] Tumor cell analysis showed biallelic inactivation of HNFα. Micro/small HNF1α-inactivated HCAs have also been incidental findings in pathological liver resected specimens.[46]

United States data

Hepatocellular adenomas (HCAs) (hepatic adenomas) are extremely rare, occurring in less than 0.007-0.012% of the population.[1] The overall incidence in women not taking OCPs is estimated at 1-1.3 per million, but in women taking oral contraceptive pills (OCPs), it is estimated at 34 per million[3] —with increased risk associated with higher-dose estrogen exposure and duration of exposure.[8] However, more recent epidemiologic studies are lacking. Despite the introduction of lower-dose hormonal contraceptives, hepatic adenomas may be detected more frequently owing to the increased routine use of medical imaging as well as the increasing incidence of obesity and metabolic syndrome.[10]

Race-, sex-, and age-related demographics

No racial predisposition exists for hepatic adenomas, but a large review of HCAs from 1998 to 2008 that compared data from China, Europe, North America, and South-East Asia found a male predominance of HCA in the Chinese population, which is in contrast to the female predominance everywhere else. This has been speculated to be due to the birth control policy in China and as well as the limited use of OCPs.[47]

Approximately 90% of patients with hepatic adenomas are female.[20] HCA in males is more likely to be associated with anabolic-androgenic steroid use and glycogen storage disease (GSD).[11, 20]  Male HCA is also most often associated with the β-HCA subtype, with increased association for malignancy transformation.[20, 26]

Most affected patients are aged 20-50.[2]

Complete resolution of hepatocellular adenoma (HCA) (hepatic adenoma) is atypical. Prognosis depends on modification of risk factors and monitoring of lesions to reduce the risk of complications, which mainly include hemorrhage and malignant transformation.

Morbidity/mortality

Hepatic adenomas are relatively well vascularized, thus hemorrhage is a common complication. Intraperitoneal bleeding is seen likely due to lack of a defined, fibrous capsule.[48] In a systematic review comprising 1176 patients, the overall frequency of hemorrhage was 27.2%. Hemorrhage occurred in 15.8% of all HCA lesions; rupture and intraperitoneal bleeding were reported in 17.5% of patients. Interestingly, a similar overall frequency of patients with HCA hemorrhage (25.4%) were found when earlier studies with oral contraceptive pills (OCPs) with higher estrogen content were excluded.[48] Risk factors involved in an increased risk of HCA hemorrhage include tumor size of at least 5 cm, location in the left hepatic lobe, and exophytic growth of the tumor.[48, 49]

Although a tumor size of 5 cm is the standard for resection owing to the increased risk of hemorrhage and malignant transformation, multiple case series have reported hemorrhage in hepatic adenomas smaller than 5 cm, even as small as 1 cm[50] ; however, the risk appears to be minimal. Size—not number of lesions—appears to be related to the risk of hemorrhage. Multiple studies did not find a difference between patients with a single or multiple HCAs.[51, 52, 53]

Rooks et al estimated mortality to be 21% after HCA rupture and intraperitoneal bleeding.[3] Although data are from limited case series of ruptured HCAs, mortality for emergency resection has been estimated between 5% and 10%, whereas that for elective surgery has been estimated to be less than 1%.[54] In cases of high surgical risk or anatomic difficulty, nonsurgical modalities such as embolization and conservative management with adequate resuscitation can be efficacious.[1] Following a massive hemorrhage with intervention or conservative management, the rebleeding risk has been estimated to be around 4.3%, with elective therapy only indicated for persistent size of 5 cm and larger.[55]

The overall risk of malignant transformation is 4.2%, based on a systematic review incorporating reports on malignant degeneration of HCA into hepatocellular carcinoma (HCC), with only 4.4% of these malignant transformations occurring in lesions smaller than 5 cm in diameter.[56] This transformation rate appears to have remained stable over the past four decades as HCA has been closely monitored, based on resected HCA specimens.[57] Malignant transformation is predominantly found among males, tumors with diameter of at least 5 cm, and with the β-HCA subtype.[31, 56] Somatic promoter mutations in telomerase reverse transcriptase (TERT) have been identified as a late event in conjunction with activating CTNNB1, which is associated with progression of HCA to HCC.[58]  The risk of malignant transformation remains even after contraceptive or steroid use has been discontinued.[59]

Pregnancy has been associated with hepatic adenoma growth, due to exposure to hormones. As growth of HCA is associated with an increased risk of rupture, this is of prime importance in pregnant patients, as rupture of the tumor during pregnancy has a 44% maternal mortality and a 38% fetal mortality.[60] For pregnant patients with HCA smaller than 5 cm, there appears to be minimal maternal risk and no risk to the fetus in a 2020 prospective study.[61] In a setting where surgery is indicated, especially with lesions in the periphery of the hepatic anatomy, it is recommended the operation be planned prior to 24 weeks' gestation to reduce the risk of fetal complications.[20]

The clinical presentation of hepatocellular adenoma (HCA) (hepatic adenomas) varies widely. Salient features of the history and physical examination may include the following:

• Pain may be present in the right upper quadrant or epigastric region.

• Patients may notice a palpable mass. Lesions may also be discovered incidentally during an abdominal imaging study for an unrelated reason.

• History of birth control or anabolic steroid use should be elicited in patients with suspected HCAs.

• Patients may also present with severe, acute abdominal pain with bleeding into the abdomen, which results in signs of shock (eg, hypotension, tachycardia, diaphoresis).

• Hemoperitoneum occurs more frequently if the patient is taking a high-dose oral contraceptive pill (OCP), is actively menstruating or pregnant, or is within 6 weeks postpartum. Location of the lesion also is important, with those near the surface of the liver more prone to causing hemoperitoneum.

The physical examination findings in patients with hepatocellular adenomas (HCAs) (hepatic adenomas) are often nonspecific. Patients may be asymptomatic, or they may appear ill, with pallor and abdominal distress. Note the following:

• Vital signs with tachycardia, hypotension, or orthostasis (concerning for active hemorrhage)

• Anicteric sclera (jaundice has been reported due to compression of the tumor on the biliary tree)

• Pale conjunctiva, if hemorrhage has occurred

• Right hypochondrial mass, with or without tenderness

• Hepatomegaly

• Fluid wave (in cases of hemoperitoneum)

• Peritoneal signs, including guarding or rebound in cases of tumor rupture

• Skin findings: Grey Turner sign or Cullen sign in cases of hemoperitoneum

Serologically, hepatocellular adenomas (HCAs) (hepatic adenomas) are a diagnosis of exclusion. No specific serologic studies exist.

Abnormal liver function tests, especially elevations in γ-glutamyl transferase and alkaline phosphatase are seen, likely due to mass effect of the tumor.[41]

Inflammatory syndrome, which can be characterized by serum elevations in C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), white blood cells (WBCs), or others, may be seen predominantly in the inflammatory subtype (I-HCA).[41, 64]

Serum alpha-fetoprotein (AFP) levels are within the reference range in patients with hepatic adenoma. Elevations of AFP should prompt consideration of either a primary hepatocellular carcinoma (HCC) or an adenoma that has undergone malignant transformation.[2] However, an AFP level within the reference range does not eliminate HCC from the differential diagnosis.

Elevated serum carcinoembryonic antigen (CEA) levels suggest metastasis from the colon.

Serologies for amebiasis and echinococcosis should be considered if the lesion appears cystic or there is clinical concern for these diseases.

Findings of hepatocellular adenomas (HCAs) (hepatic adenomas) on imaging studies have been difficult to characterize due to their heterogeneous nature. Advances in contrast-enhanced magnetic resonance imaging (MRI) have made imaging studies more prominent in the diagnosis of HCAs, with regard both to specific subtypes and differentiation from focal nodular hyperplasia (FNH). Utilization of imaging techniques have reduced the need for patients to undergo biopsy and the subsequent associated risks.[65, 66]

Ultrasonography

The ultrasonographic appearance of hepatic adenoma is nonspecific and generally requires further investigation. The tumors can appear well demarcated if hyperechoic in the presence of steatosis; HCAs will appear anechoic if intralesional hemorrhage is present.[65] Doppler flow patterns in HCAs show peripheral vessels and venous flow in most cases, as compared with the "spoked-wheel" arterial pattern noted in FNH.[67]

Contrast-enhanced ultrasonography (CEUS)

CEUS involves using a microbubble contrast medium that reveals rapid arterial enhancement progressing from the periphery to the center of the tumor, which correlates with the presence of higher concentrations of multiple, thin arteries in the periphery of HCA.[68, 69, 70, 71, 72] This finding is in contrast to the findings in FNH, which typically show hyperperfusion from a large feeding artery in the arterial phase from the center outward, producing a "spoked-wheel" appearance.[70]  Hepatic adeomas can have a gradual washout phenomenon due to missing portal veins in the late phase; for this reason, HCA enhancement patterns can be confused with malignancy.[68, 71] The reported sensitivity in differentiating HCA from FNA with CEUS ranges from 86% to 95%, with a specificity of 74-79%.[73]

Computed tomography (CT) scanning

On noncontrast CT scans, HCA appears as a well-demarcated mass with low density and no lobulation.[74] On contrast-enhanced, multiphase, CT images, the tumor shows an early peripheral enhancement with a centripetal pattern during the portal venous phase. It then fades to isodensity in the portal or delayed phase. Rarely, the lesion can have a central necrotic area or calcifications.[65, 74, 75]

Magnetic resonance imaging (MRI)

The MRI appearance of hepatic adenoma is variable, owing to the presence or absence of hemorrhage. Hyperintense heterogeneous signals on T1- and T2-weighted imaging are often due to HCAs containing intratumoral lipids, which differentiates HCA from FNH.[76, 77] Hemorrhagic HCAs may also have hyperintense T1 imaging with subcapsular hemosiderin rings.[66]

Specific MRI contrast agents can be administered to further characterize HCAs. Administration of Kupffer cell–specific MRI agents (superparamagnetic iron oxides [SPIOs] and ultra-small superparamagnetic iron oxides [USPIOs]) typically show no uptake due to a lack of endothelial-reticular cells, resulting in decreased T2 signal intensity.[75] Gadolinium-enhanced dynamic gradient-echo MRI may display early arterial enhancement, resulting in visualization of the peritumoral vessels characteristic of HCA.[78]

A prospective study showed administration of gadoxetate disodium in a standard series combined with hepatobiliary phases helped to differentiate HCA from FNA in lesions larger than 2 cm.[66] Both gadobenate dimeglumine and gadoxetic acid are also liver-specific contrast agents; when utilized in the hepatobiliary phase, these agents have shown equivalent efficacy in differentiating HCA from FNH,[79]  although a 2019 study has shown the possible superiority of gadoxetic acid.[80] Additionally, gadoxetic acid-enhanced MRI (EOB-MRI) has been found to be most cost effective in a 2018 study, although there was similar effectiveness among the EOB-MRI, conventional MRI, and biopsy strategies in patients with incidentally detected liver lesions in a noncirrhotic liver.[81]

MRI can also be helpful in differentiating specific subtypes of HCA, which improves their clinical characterization and follow-up without the need for biopsy.[1, 65, 76]  However, newer discoveries of further subtype classifications has complicated MRI usefulness in differentiation.[41, 20] Any inconclusive imaging should be considered for biopsy, with an informed discussion with the patient of the risks involved.[65]

In HCA inactivated for hepatocyte nuclear factor 1α (H-HCA), typical findings on MRI include loss of signal on chemical shift as well as moderate arterial enhancement without persistent enhancement in the delayed phase. In a study by Laumonier et al, oss of chemical shift in H-HCA, which is associated with the presence of steatosis, had a sensitivity of 86.7% and specificity of 100%.[76]

In inflammatory hepatic adenomas (I-HCA), typical findings on MRI include a markedly hyperintense appearance on T2-weighted images, with a strong peripheral signal as well as persistent enhancement in delayed phase. If both findings are present, Laumonier et al found a sensitivity of 85.2% and specificity of 87.5%.[76]  Ba-Ssalamah et al reported that use of gadoxetic acid resulted in lower sensitivity (80.9%) and specificity (77.3%).[82]

In β-catenin activated HCA (β-HCA), the MRI findings depend on the subtype. The inflammatory subtype of β-HCA has the same appearance as I-HCA. For noninflammatory β-HCA, typical MRI findings show a heterogeneous appearance in all sequences, no signal dropout on chemical shift, isointense appearance on T1- and T2-weighted images, and strong arterial enhancement and delayed washout.[76] Note that newly developed subtypes of β-HCA may not be able to be differentiated from each other and HCC with imaging alone, therefore a high index of suspicion is required.[20, 82]

Nuclear scans

Nuclear scans are rarely diagnostic for hepatic adenomas; however, when performed, HCAs have decreased colloid uptake and thus appear as cold nodules on technetium-99m (99mTc) sulfur colloid scans. This distinguishes them from FNH, which typically shows normal or increased colloid uptake. Decreased uptake in HCA is due to the altered blood flow through the lesions and the lack of phagocytic activity of Kupffer cells.[75, 83]

Although subtyping of hepatocellular adenoma (HCA) (hepatic adenoma) has not resulted in significant clinical management changes and imaging shows promise for noninvasive characterization, in the setting of indeterminate results or concern for malignancy, it is reasonable to perform biopsy.[20]

Initial differentiation from the surrounding hepatocytes can be accomplished with the use of CD34, which shows increased sinusoidal staining in both benign and malignant hepatocellular tumors.[84]

Immunohistochemistry

Immunoexpression of liver-type fatty acid binding protein (L-FABP) is reduced in HCA inactivated for hepatocyte nuclear factor 1α (H-HCA), but it will be present in the surrounding hepatocytes, helping to differentiate this subtype from other HCA subtypes as well as from the surrounding hepatic tissue.[85] H-HCA also shows negative staining for glutamine synthetase (GS), serum amyloid A (SAA), and C-reactive protein (CRP).[27]

A heterogeneous staining pattern of β-catenin in the nucleus and cytoplasm is a defining feature of β-catenin activated HCA (β-HCA).[27] GS, an enzyme involved in nitrogen metabolism, is also useful in differentiating β-HCA from other hepatic adeoma subtypes and focal nodular hyperplasia (FNH).[27]  FNH has a maplike distribution that is distant from fibrous bands or arteries, whereas β-HCAs have a more diffuse, strong staining pattern.[86, 87] Relatively recent studies have shown the strongest GS positivity to be found in CTNNB1 mutations in exon 3.[41]

Immunoexpression of the acute phase reactants SAA and CRP are defining features of inflammatory adenoma (I-HCA),[41] differentiating it from other subtypes as well as surrounding hepatocytes. Notably, L-FABP expression is increased and GS is usually not expressed.[27] The finding of elevated GS and/or heterogeneous β-catenin should raise suspicion for mixed I-HCA and β-HCA.[27, 41]

Differentiation from hepatocellular carcinoma (HCC)

Differentiation of HCC from HCA is extremely important, especially in β-HCA, where HCC transformation is a known complication.[88] Generally, HCC demonstrates a loss of the reticulin framework on reticulin staining, whereas HCA and FNH maintain an intact reticulin network.[89] Glycipan-3 (GPC3) is a cell surface glycoprotein that is overexpressed in HCCs. Wang et al reported that GPC3 staining was not present in all 110 cases of benign liver tumors in their study, yet the staining was positive in 75.7% of HCCs.[90] Lagana et al demonstrated GPC3 positivity had a sensitivity of 43% and specificity of 100% when differentiating low-grade, well-differentiated HCC from HCA.[91]  Similarly, diffuse nuclear heat-shock protein-70 (HSP-70) staining has shown a 46% sensitivity and 100% specificity when differentiating low-grade, well-differentiated HCC from HCA.[91]

Tretiakova et al assessed tumor cell expression patterns of E-cadherin and matrix metalloproteinases (MMPs)-1,-2,-7 and -9 in a variety of liver tumors and controls, reporting that HCA was characterized by an absence of MMP-7 expression, whereas HCC without cirrhosis had low MMP-9 expression.[92]

Agrin is a proteoglycan component of bile duct and vascular basement membranes of the liver that is deposited in microscopic blood vessels of HCC. Tatrai et al reported that the combination of immunohistochemical staining for agrin and CD34 was helpful for differentiating HCC from benign lesions when the diagnosis was equivocal.[93] In addition, agrin appeared to be more sensitive than GPC-3, as agrin is diffusely deposited in all malignant lesions, whereas GPC-3 may only be present in a few cells.

Ahmad et al reported that a combination of cytokeratin 7 and 9 with neuronal cell adhesion molecule immunostains were very helpful not only in differentiating normal liver tissue from tumors but also in differentiating hepatic adenomas from FNH.[94]

Results of histologic evaluation with a fine needle biopsy are nondiagnostic and insensitive for hepatocelllular adenoma (HCA) (hepatic adenoma) because the mass comprises normal-appearing hepatocytes.[95] Core needle biopsies, especially when combined with immunohistochemistry, can be considered in cases of nondiagnostic imaging or concern for malignancy.[95] Additionally, indeterminant lesions on imaging do not warrant empiric ablation without confirmation of the diagnosis; core biopsy should be considered in these cases.[20]

In a retrospective review (2000-2013) of patients undergoing hepatic mass biopsy revealing HCA, Doolittle et al investigated the safety and outcomes of biopsy of these lesions.[96] Of 60 identified patients with a total of 61 biopsy-proven hepatic adenomas, they found that one patient (2%) had a single major complication and six patients (10%) had a minor complication. In addition, there were six (10%) discordant biopsy results.[96]

Complete resection of HCA or suspected HCA remains the gold standard of diagnosis, but it is not always required for lesions smaller than 5 cm or those not increasing in size.[20]

Upon gross examination, hepatocellular adenomas (HCAs) (hepatic adenomas) appear as sharply circumscribed, light brown to yellow tumors that are soft in consistency and often lack a true fibrous tumor capsule.[97] Although these lesions are usually solitary, HCAs may be multiple, with sizes ranging from 1 to 30 cm, although most are between 8 and 15 cm. Hepatic adenomas tend to be larger in women taking oral contraceptive pills (OCPs). They also occur more frequently in the right lobe and are usually subcapsular, although pedunculated adenomas have also been described.[2]

On microscopic examination, the hallmark of adenomas is the normal appearance of the hepatocytes. These are arranged in sheets, have no malignant features, tend to be larger than normal hepatocytes. Their cytoplasm often contains fat or glycogen and thus may appear relatively pale due to abundant glycogen stores when compared with normal hepatocytes. Generally, few, if any, portal tracts are present, and no central veins or bile ducts should be present.[27, 98] However, Bisceglia et al reported that subtypes of HCAs may have cytokeratin 7-positive ductules; they called hepatic adenoma with ductal/ductular differentiation.[99]

Peliosis hepatis (rare vascular condition with multiple blood-filled cavities scattered throughout the liver) may occasionally be seen and this is most often associated with the β-catenin activated HCA (β-HCA) and inflammatory adenoma (I-HCA) subtype (previously known as telangiectatic focal nodular hyperplasia [FNH]).[32, 100] Vessels, when observed, tend to have thickened walls. Areas of thrombosis and infarction may be noted. Most hepatic adenomas contain a variable degree of microscopic collections of fat.[101] Differentiation from a high-grade hepatocellular carcinoma (HCC) can be difficult, if not impossible. Hepatic adenomas tend to lack malignant-appearing mitotic structures, the cell plates are generally only two cells thick, and no cellular infiltration (invasion) into the capsule or surrounding liver parenchyma occurs. Unfortunately, these features may also be seen in HCC, especially if it is well differentiated.[102]

Hypervascularity is present upon the surface of the lesion. Because hepatic adenomas contain no portal vein branches, their blood supply is entirely arterial. The tendency for these lesions to bleed may be related to poor connective tissue support and their increased vasculature, which is made up of thin-walled, dilated sinusoids carrying blood at arterial pressure.[27]

Imaging and follow-up

Baseline imaging with contrast enhanced magnetic resonance imaging (MRI) is recommended at the initial diagnosis of hepatocellular adenoma (HCA) (hepatic adenoma), to aid in characterization of lesion and possible subtype determination. It is important to recognize the size of the tumor as well as any exophytic protrusion, as these features are associated with an increased risk of hemorrhage.[48, 49]  

For women with hepatocellular adenomas (HCAs) (hepatic adenomas) with a baseline size smaller than 5 cm, rupture and subsequent hemorrhage are rare, and medical management is reasonable with appropriate imaging followup.[103] For tumors with multiple lesions, management is based on the size of the largest lesion, rather than on the number of lesions, as previous studies have not shown a significant increased risk of hemorrhage or malignancy based on number alone.[32]

For all presumed HCAs, the 2016 European Association for the Study of the Liver (EASL) guidelines recommend repeat contrast-enhanced magnetic resonance imaging (MRI) 6 months from the baseline diagnosis to assess for persistent size of at least 5 cm or for increasing diameter size (≥20%) per Response Evaluation Criteria in Solid Tumors (RECIST) criteria for solid malignant tumors.[20, 104] The RECIST (version 1.1) criteria note that the 20% or greater increase in diameter should also be accompanied by a 5-mm absolute increase in diameter.[104]

A definition for stable disease is lacking; however, the 2016 EASL guidelines recommend annual imaging if the hepatic adenoma is stable 12 months from the initial diagnosis. Overall, the initial diagnosis would thus involve a baseline imaging study, followed by imaging at 6 and 12 months following baseline, and then annual imaging, if stable. Imaging intervals can be lengthened to every 2 years if the HCA size is stable after 5 years.[105] Ultrasonography is acceptable if the lesion is clearly defined.[20]  The 2014 American College Gastroenterology (ACG) guidelines slightly differ from the EASL's, recommending computed tomography (CT) scanning or MRI at 6-12 month intervals for at least 2 years, followed by annual imaging based on tumor growth and stability.[1, 106]

General measures

In women, HCAs smaller than 5 cm are less likely to rupture or progress to hepatocellular carcinoma (HCC).[56] Women should stop using any medications implicated in HCA formation, which most often includes oral contraceptives. This cessation allows for regression in the size of the majority of the tumors, although complete resolution is atypical.[20] Repeat imaging following discontinuation of causative medications should follow in 6-12 months to ensure stability of the hepatic adenoma. Note that the risk of malignant transformation or even possible HCA enlargement remains even after the contraceptive or steroid use has been discontinued.[59, 107, 108]

Women with HCAs smaller than 5 cm and who have a body mass index (BMI) over 25 kg/m2 should be encouraged to maintain a healthy body weight.[20] If β-catenin activated HCA (β-HCA) is confirmed, curative treatment or resection should be considered regardless of tumor size.[1, 20] Symptomatic HCA should be considered for surgical resection as well.[52]

In men, resection or curative therapy should be pursued regardless of tumor size, owing to a significant risk of malignant transformation in this population.[26]

Hemorrhage

Do not delay adequate resuscitation with intravenous (IV) fluids and blood products if any concern for active hemorrhage of HCA is suspected. Prompt imaging with CT or MRI should be pursued. In cases of hemodynamic instability or hemorrhage not responding to resuscitation as well as lesions with difficult anatomic position, transarterial embolization or other noninvasive procedures can be performed to control bleeding.[109] Hepatic adenomas of 5 cm and larger should be considered for surgical resection due to their propensity for rebleeding.[1, 20, 110]

Pregnancy

Given the tendency of HCAs to enlarge and the increased risk of rupture and hemorrhage during pregnancy, close monitoring of these women is required along with a multidisciplinary approach.[111]  The 2016 EASL guidelines recommend close monitoring with ultrasonography every 6-12 weeks to monitor for changes in tumor size. For HCAs smaller than 5 cm without growth or exophytic location, vaginal delivery can be pursued.[20, 111] If the HCA enlarges significantly, embolization can be considered. If the pregnancy is at less than 24 weeks' gestation, surgical intervention can be considered to reduce the maternal and fetal risk of ionizing radiation.[20, 112]

There are no consensus guidelines for pursuing pregnancy with known hepatic adenoma, especially if it is at least 5 cm. In this setting, discussion regarding surgical resection prior to pregnancy may be most appropriate. A 2020 prospective study that evaluated pregnant women with tumors smaller than 5 cm found minimal maternal risk and no risk to the fetus.[61] The study recommended contrast-enhanced MRI prior to pregnancy to ensure an accurate diagnosis and to differentiate HCA from focal nodular hyperplasia (FNH), as well as serial ultrasonographic examinations during pregnancy to monitor for changes in the size of the lesion.[61]  HCA rupture and hemorrhage during pregnancy requires appropriate hemodynamic resuscitation and noninvasive embolization when appropriate.[113]

Surgical indications and considerations

Surgical management of hepatocellular adenoma (HCA) (hepatic adenoma) is indicated regardless of tumor size in men,[26]  as well as with confirmation of β-catenin activated HCA (β-HCA) subtype,[1, 20] symptomatic HCA,[52] and residual lesion following HCA hemorrhage with intervention.[20]  Patients with significantly elevated serum alpha-fetoprotein (AFP) levels should undergo further evaluation and consideration of resection regardless of HCA size due to the concern for underlying hepatocellular carcinoma (HCC).

Surgical management of HCA is indicated when its diameter is at least 5 cm or has an increasing diameter (≥20%) per Response Evaluation Criteria in Solid Tumors (RECIST) criteria for solid malignant tumors.[20, 104] Increasing diameter should be reevaluated 6-12 months following cessation of causative agents regardless of HCA size. Although a tumor diameter of 5 cm and larger is an indication for surgery, for patients with an HCA of at least 5 cm with steroid exposure, reevaluation in 6-12 months is reasonable based on patient preference, with the understanding that HCC can develop and the diameter can increase regardless of steroid cessation.[20]

In a multicenter study of 124 patients, Deneve et al reported that factors that predisposed HCAs to rupture were larger tumors and recent hormone use in women.[51] The investigators recommended surgical resection when HCAs approached 4 cm in size or if hormonal therapy was required.

Cho et al reported their experience with the management and outcomes of 41 patients with hepatic adenomas treated at the University of Pittsburgh between 1988 and 2007, in which surgical resection was preferable to observation if patients' comorbidities and the anatomic location of the tumor were acceptable due to risks of hemorrhage (29%) and malignancy (5%).[50]

Liver transplantation

In rare patients with glycogen storage disease (GSD), or other underlying liver disease, liver transplantation may be the only intervention that may remove all lesions and cure the underlying metabolic defect.[114] It is important to monitor these patients closely, as evidence exists showing the chromosomal aberration of simultaneous gain of 6p and loss of 6q could be high risk in the progression from HCA to HCC, regardless of metabolic control.[45] Liver transplantation has also been successfully performed for spontaneous intrapartum rupture of a hepatic adenoma.[115]

Timing and approach

With regard to the timing of resection, Klompenhouwer et al have suggested that a 6-month cut-off point in women is too early for assessment of regression of HCAs of 5 cm and larger.[116] Rather, they indicate that in women with typical, non-β-HCAs, regardless of the baseline diameters, the cut-off point may be extended to up to 12 months.[116]

The majority of tumors can be resected locally or with segmental partial lobectomy. In cases of multiple hepatic adenomas, resection of the largest lesions may be the most appropriate approach.[20, 29]  Data from limited case series show mortality for emergency resection of ruptured HCA is about 5-10%, whereas mortality for elective surgery has been estimated to less than 1%.[54]

In a retrospective (1989-2013) multi-institutional European study of all patients who had undergone open or laparoscopic hepatectomies for hepatic adenomas to investigate the effects of the surgical approach on postoperative morbidities, Landi et al found that open surgery and laparoscopy showed similar postoperative morbidity rates and severities.[117] However, laparoscopy was associated with significantly less blood loss, a reduced need for transfusion, and a shorter hospital stay.[117]

Radiofrequency (RF) ablation

RF ablation can be used effectively in the treatment of hepatic adenoma.[118] However, multiple sessions are often required, and signs of residual adenoma might persist in some patients despite repetitive treatment. RF ablation may be especially beneficial in cases not amenable to surgery or in patients who would require major hepatic resection. Cases not amenable to surgery include those with centrally located lesions or the presence of multiple HCAs in both lobes of the liver.

In a retrospective, single-arm study of 36 patients with 58 HCAs who underwent 44 procedures with percutaneous thermal ablation, Mironov et al reported a primary efficacy of 88% and a secondary efficacy of 100%, with a major complication rate of 4.5% (postprocedural hemorrhage).[119] At a median follow-up of 1.7 years, there was 100% clinical efficacy with no reports of malignant transformation, adenoma-related hemorrhages, or deaths.

The American College of Gastroenterology (ACG) issued clinical guidelines for the diagnosis and management of focal liver lesions in 2014.[1] The European Association for the Study of the Liver (EASL) released clinical practice guidelines on the management of benign liver tumors in 2016.[20]  Their recommendations include the following:

• Imaging of hepatocellular adenoma (HCA) (hepatic adenoma) with magnetic resonance imaging (MRI) is superior to all other imaging modalities and offers subtype differentiation in many cases, especially with the hepatocyte nuclear factor (HNF) 1a-mutated HCA (H-HCA) and inflammatory HCA (I-HCA) subtypes. β-catenin activated HCA (β-HCA) subtype is not well identified by any imaging technique and should be carefully looked for given its association with hepatocellular carcinoma (HCC).[20]

• Once HCA is diagnosed, lifestyle changes including discontinuation of oral contraceptive pills (OCPs) and weight loss should be advised.[1, 20] Further management is guided by sex, size, pattern of progression, and subtype.[20] The routine use of biopsy is not recommended but may be considered in cases with inconclusive imaging or when biopsy findings may change management decisions.[1]

• HCA resection is recommended in men and in patients with proven β-catenin mutation subtype, regardless of size.[20]

• For women with HCA, initial lifestyle changes and 6 months of observation if no high-risk features are present is advised. Resection may be considered for HCAs of at least 5 cm or those that continue to grow. HCAs smaller than 5 cm should be followed with imaging, initially at 1 year from diagnosis and then annually thereafter.[20]  The ACG guidelines recommend considering follow-up imaging every 6-12 months, with subsequent intervals based on the stability of the lesion.[1] Pregnancy is not absolutely contraindicated for HCAs smaller than 5 cm; however, an individual approach is recommended.[1]

• Patients with multiple HCAs should have their management based on the size of the largest tumor, and hepatic resection can be considered for the largest adenomas. Hepatic resection may also be considered in patients with unilobular disease or widespread HCA. Liver transplantation is not recommended for patients with multiple HCAs; however, it may be considered if underlying liver disease exists. Patients with bleeding HCAs and hemodynamic instability should undergo  tumor embolization; if residual lesion is found on imaging, resection may be required.[20]